P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular disease

ABSTRACT

The invention provides piperidine compounds of general formula (I) in which A, B, X, Y, Z, R, R1 and R2 are as defined in the specification, their use as medicaments, compositions containing them and processes for their for their preparation.

The present invention relates to piperidine derivatives, a process fortheir preparation, pharmaceutical compositions containing them, aprocess for preparing the pharmaceutical compositions, and their use intherapy.

The P2X₇ receptor (previously known as P2Z receptor), which is aligand-gated ion channel, is present on a variety of cell types, largelythose known to be involved in the inflammatory/immune process,specifically, macrophages, mast cells and lymphocytes (T and B).Activation of the P2X₇ receptor by extracellular nucleotides, inparticular adenosine triphosphate, leads to the release ofinterleukin-1β (IL-1β) and giant cell formation (macrophages/microglialcells), degranulation (mast cells) and L-selectin shedding(lymphocytes). P2X₇ receptors are also located on antigen-presentingcells (APC), keratinocytes, salivary acinar cells (parotid cells) andhepatocytes.

It would be desirable to make compounds effective as P2X₇ receptorantagonists for use in the treatment of inflammatory, immune orcardiovascular diseases, in the aetiologies of which the P2X₇ receptormay play a role.

In accordance with the present invention, there is therefore provided acompound of formula (I):

where

A is phenyl or a 5- or 6-membered heterocyclic ring containing one ortwo heteroatoms selected from O, N or S; and optionally substituted byC₁₋₆alkyl, halogen, nitro, amino, alkylamino, CF₃, SO₂Me, NHSO₂Me orcyano;

B is C═O, NH or SO₂;

X is C═O, CH(Me), O or (CH₂)p where p is 0 or 1;

Y is O, CH₂, NH or S;

Z is C═O or SO₂, provided that when Z is C═O, then Y is O, CH₂ or S;

R is hydrogen or C₁₋₆alkyl;

R¹ is hydrogen, halogen;

R² is phenyl optionally substituted by CO₂H, CO₂alkyl, CONH₂ or R² isOH, NHR³, NHCH(R⁴)(CHR⁵)_(n)R⁶, NH—R⁷—R⁸, SO₂NHalkyl, NHCOalkyl,NHSO₂alkyl, morpholine, NR⁹R¹⁰, piperazine substituted by phenyl,alkoxyphenyl, pyridyl or fluorophenyl;

n is 0, 1 or 2;

R³ is hydrogen, a bi- or tricyclic saturated ring system optionallycontaining a nitrogen atom, piperidinyl, alkylpyrollidine,ethynylcyclohexyl, a 5-membered aromatic ring containing 2 or 3heteroatoms, C₄₋₆ cycloalkyl optionally substituted by alkyl, cyano orhydroxy, or C₁₋₈alkyl optionally containing an oxygen atom in the alkylchain and being optionally substituted by one or more substituentsselected from ethynyl, cyano, fluoro, di-alkylamino, hydroxy, thioalkyl,CO₂R¹¹ or CONH₂;

R⁴ is hydrogen or alkyl optionally substituted by hydroxy or alkoxy;

R⁵ is hydrogen or hydroxy;

R⁶ is CO₂R¹¹, NHCO₂R¹², CONH₂ or a 5 or 6-membered saturated ringcontaining an oxygen atom, a 5-membered heterocyclic ring containing oneor two heteroatoms selected from O, N or S, or phenyl optionallysubstituted by one or more groups selected from alkyl, hydroxy, amino,alkoxy, or nitro;

R⁶ is alkyl;

R⁷ is a cyclopentane ring;

R⁸ is phenyl;

R⁹and R¹⁰ are independently hydrogen, benzyl, alkenyl, cycloalkyl, alkyloptionally substituted by hydroxy, alkoxy, cyano, dialkylamino, phenyl,pyridyl or CO₂R¹¹ or R⁹ and R¹⁰ together form a 5- to 7-memberedsaturated or partially saturated ring optionally containing a furtherheteroaton and optionally substituted by one or more groups selectedfrom alkyl (optionally containing an oxygen atom in the chain andoptionally substituted by hydroxy), COalkyl, CO₂R¹¹, COR¹³R¹⁴, CHO orpiperidine,

R¹¹ is hydrogen or alkyl;

R¹² is alkyl; and

R¹³ and R¹⁴ are independently hydrogen or alkyl, and pharmaceuticallyacceptable salts and solvates thereof

In the context of the present specification, unless otherwise indicated,an alkyl substituent or alkyl moiety in a substituent group may belinear or branched and may contain up to 6 carbon atoms, examples ofwhich include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, n-pentyl and n-hexyl.

Suitably A is phenyl or a 5- or 6-membered heterocyclic ring containingone or two heteroatoms selected from O, N or S; and optionallysubstituted by C₁₋₆alkyl, halogen, nitro, amino, alkylamino, CF₃, SO₂Me,NHSO₂Me or cyano. Examples of suitable 5- or 6-membered heterocyclicrings include. Preferably A is optionally substituted phenyl, morepreferably A is phenyl substituted by a nitro group.

Suitably B is C═O, NH or SO₂. Preferably B is C═O.

Suitably X is C═O, CH(Me), O or (CH₂)p where p is 0 or 1, Y is O, CH₂,NH or S and Z is C═O or SO₂. Examples of groups formed by X, Y and Zinclude benzoxazinone and dihydroquinoline. Preferably X is CH₂, Y is Oand Z is C═O such that X, Y and Z together form part of a benzoxazinonering which can be optionally substituted by methyl.

Suitably R is hydrogen or C₁₋₆alkyl, preferably R is hydrogen.

Suitably R¹ is hydrogen or halogen, preferably R¹ is hydrogen.

Suitably R² is phenyl optionally substituted by CO₂H, CO₂alkyl, CONH₂ orR² is OH, NHR³, NHCH(R⁴)(CHR⁵)_(n)R⁶, NH—R⁷—R⁸, SO₂NHalkyl, NHCOalkyl,NHSO₂alkyl, morpholine, NR⁹R¹⁰, piperazine substituted by phenyl,alkoxyphenyl, pyridyl or fluorophenyl. Preferably R²is NR⁹R¹⁰ where oneof R⁹ or R¹⁰ is hydrogen and the other is alkyl such as CH(CH₃)₂.

Particularly preferred compounds of the invention include thoseexemplified herein both in free base form as well as allpharmaceutically acceptable salts and/or solvates thereof

According to the invention there is further provided a process for thepreparation of a compound of formula (I) which comprises reaction of acompound of formula (II):

where R, R¹, X, Y and Z are as defined in formula (I) or a protectedderivative thereof, with a compound of formula (III):

where B and R² are as defined in formula (I) or a protected derivativethereof, and L is a leaving group, and optionally thereafter in anyorder:

converting one or more functional groups into further functional groups

removing any protecting groups

forming a pharmaceutically acceptable salt or solvate.

Examples of suitable leaving groups L include halogen, OMs and OTs.Preferably L is halogen, in particular chloro.

The reaction of compounds of formula (II) and (III) is preferablycarried out in the presence of an organic amine such as a trialkylamine,for example triethylamine. The reaction is preferably carried out in aninert solvent such as NMP, DMF or dioxan preferably at elevatedtemperature, for example at the reflux temperature of the reactionmixture.

Compounds of formulae (II) can be prepared as follows:

(a) by reacting a compound of formula (IV):

 in which X, Y and Z are as defined in formula (II) or are protectedderivatives thereof, with a compound of formula (V):

 in which R²⁰ is a leaving group or an activated hydroxy group, or

(b) by reacting a compound of formula (VI):

 in which P a protecting group, with a compound of formula (VII):

 in which the groups L are leaving groups.

Compounds of formulae (IV) and (V) can be reacted under Mitsonobuconditions when R²⁰ in compound (V) is an activated hydroxy group. Forthe reaction of compounds (VI) and (VII), examples of suitable leaving Lgroups include halogen, in particular chloro, or imidazole.Alternatively triphosgene can be used. Suitable protecting groups forcompounds (V) and (VI) include t-butoxy carbonyl (Boc).

Compounds of formula (III), (IV), (V) and (VII) are prepared usingIterature procedures or are commercially available.

Functional groups can be converted into further functional groups usingprocedures known in the art. For example a carboxylic acid group can beconverted into an ester or amide using standard chemistry.

Protecting groups can be added and removed using known reactionconditions. The use of protecting groups is fully described in‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, PlenumPress (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition,T W Greene & P G M Wutz, Wiley-Interscience (1991).

Deprotection can be carried out using methods generally known in theart.

All novel intermediates form a further aspect of the invention.

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium orpotassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The compounds of the present invention are advantageous in that theypossess pharmacological activity and have utility as modulators of P2X₇receptor activity. They are therefore indicated as pharmaceuticals foruse in the treatment or prevention of rheumatoid arthritis,osteoarthritis, psoriasis, allergic dermatitis, asthma,hyperresponsiveness of the airway, chronic obstructive pulmonary disease(COPD), bronchitis, septic shock, glomerulonephritis, irritable boweldisease, Crohn's disease, ulcerative colitis, atherosclerosis, growthand metastases of malignant cells, myoblastic leukaemia, diabetes,neurodegenerative disease, Alzheimer's disease, meningitis,osteoporosis, burn injury, ischaemic heart disease, stroke, peripheralvascular disease and varicose veins.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, ashereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as hereinbefore defined in the manufacture of a medicament for use intherapy.

The invention further provides a method of effecting immunosuppression(e.g. in the treatment of rheumatoid arthritis, irritable bowel disease,atherosclerosis or psoriasis) which comprises administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined to a patient.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.10 to 70% w, of active ingredient, and, from 1 to99.95% w, more preferably from 30 to 99.90% w, of a pharmaceuticallyacceptable adjuvant, diluent or carrier, all percentages by weight beingbased on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administeredtopically (e.g. to the lung and/or airways or to the skin) in the formof solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

The present invention will now be further illustrated by reference tothe following examples.

EXAMPLE 12-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoicacid

A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride (J.Med. Chem. 1998, 2157) (0.8 g),2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.9 g) and triethylamine (0.8ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for72 h. The mixture was partitioned between ethyl acetate and dilutehydrochloric acid, the organic layer was evaporated under reducedpressure. Purification was by chromatography eluting with 4%methanol/dichloromethane. The residue was triturated from methanol,yield 0.4 g as a solid.

MS: APCI(+ve) 502(M+1)

1H NMR: δ (CDCl3/DMSO-d6) 8.13-8.05(2H, m), 7.80(1H, d), 7.70-7.57(2H,m), 7.43-7.33(2H, m), 7.23-7.09(4H, m), 5.12(2H, s), 4.20-4.08(1H, m),3.55(2H, d), 3.21(2H, t), 2.90-2.80(2H, m), 1.97(2H, d)

MP: 243-4° C.

EXAMPLE 21-{1-[2-Nitro-4-(phenylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

The title compound was prepared from1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.3g) and 4-chloro-3-nitrobenzophenone (0.29 g) using the method ofexample 1. Yield 0.25 g as a solid.

MS: APCI(+ve) 458(M+1)

1H NMR: δ (CDCl3/DMSO-d6) 8.28(1H, d), 7.98(1H, dd), 7.78-7.75(2H, m),7.63-7.60(1H, m), 7.53-7.50(2H, m), 7.38(1H, t), 7.22-7.10(4H, m),5.11(2H, s), 4.25-4.19(1H, m), 3.61(2H, d), 3.23(2H, t), 2.93-2.84(2H,m), 1.98(2H, d)

MP: 272-3° C.

EXAMPLE 3 Methyl2-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoate

The product from example 1 was added to methanolic hydrogen chloride andthe mixture stirred overnight. The solvent was removed under reducedpressure and the residue purified by chromatography. Yield 0.03 g.

MS: APCI(+ve) 516(M+1)

1H NMR: δ (CDCl₃) 8.10-8.07(2H, m), 7.91(1H, dd), 7.68-7.57(2H, m),7.39-7.35(2H, m), 7.19-7.09(4H, m), 5.29(2H, s), 4.22-4.17(1H, m),3.75(3H, s), 3.57(2H, d), 3.20(2H, t), 2.90-2.81(2H, m), 1.96(2H, d)

MP: 177-9° C.

EXAMPLE 42-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzamide

A solution of the product from example 1 (0.9 g) and carbonyldiimidazole(1.1 equiv.) in dichloromethane (4 ml) was stirred at room temperaturefor 1 h, poured onto aqueous ammonia and stirred for a further 1 h. Themixture was extracted with ethyl acetate, the organics washed withwater, dried and evaporated under reduced pressure. Purification was bychromatography eluting with 2.5% methanol/dichloromethane. Yield 0.01 gas a solid.

MS: APCI(+ve) 501(M+1)

1H NMR: δ (CDCl₃) 8.08(1H, d), 7.64(1H, d), 7.58-7.34(5H, m),7.20-7.07(4H, m), 7.03(1H, s), 5.08(2H, s), 4.35(1H, s), 4.21-4.13(1H,m), 3.42(2H, d), 3.04(2H, t), 2.86-2.74(2H, m), 1.90(2H, d)

MP: 180-2° C.

EXAMPLE 5 Methyl2-({3-nitro-4-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoate

(i)2-({3-Nitro-4-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoicacid

The product was prepared from1-piperidin-4-yl-3,4-dihydroquinolin-2(1H)-one (Chem. Pharm. Bull.(1996), 44(4), 725-33) (0.45 g) and 2-(4-chloro-3-nitrobenzoyl)benzoicacid (0.6 g) using the method of example 1. Used crude.

(ii) Methyl2-({3-nitro-4-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoate

The title compound was prepared from the product from step (i) (0.2 g)which was added to methanolic hydrogen chloride and stirred at roomtemperature overnight. The solvent was removed under reduced pressureand the residue partitioned between ethyl acetate and aqueous sodiumhydrogencarbonate solution. The organics were separated, dried andevaporated under reduced pressure. Purification was by chromatography toyield 0.18 g of a solid.

MS: APCI(+ve) 514(M+1)

1H NMR: δ (CDCl₃) 8.09-8.07(2H, m), 7.92(1H, dd), 7.68-7.56(2H, m),7.37(1H, d), 7.26-7.13(4H, m), 7.03(1H, t), 4.50-4.46(1H, m), 3.74(3H,s), 3.53(2H, d), 3.18(2H, t), 2.86-2.75(4H, m), 2.61-2.57(2H, m),1.84(2H, d)

MP: 12-3° C.

EXAMPLE 62-({3-Nitro-4-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoicacid

Lithium hydroxide hydrate (3 equiv.) was added to a mixture of theproduct from example 5 step (ii) (0.15 g) in methanol/water (5.5 ml,10:1) and stirred overnight at room temperature. The solvent was removedunder reduced pressure, the residue dissolved in water and neutralisedwith dilute hydrochloric acid. The mixture was extracted with ethylacetate, dried and evaporated under reduced pressure. The residue wastriturated with ether and the solid collected. Yield 0.06 g.

MS: APCI(+ve) 500(M+1)

1H NMR: δ (CDCl₃) 8.11(2H, m), 7.86(1H, dd), 7.71(1H, m), 7.59(1H, m),7.38(1H, dd), 7.18(4H, m), 7.01(1H, m), 4.48(1H, m), 3.51(2H, m),3.16(2H, m), 2.83(4H, m), 2.27(2H, m), 1.84(2H, m)

MP: 201-203° C.

EXAMPLE 7 Methyl2-({4-[4-(7-chloro-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-3-nitrophenyl}carbonyl)benzoate

(i) 1,1-Dimethylethyl4-{[5-chloro-2-(hydroxymethyl)phenyl]amino}piperidine-1-carboxylate

N-tert-Butoxycarbonyl-4-piperidone (5.8 g), 2-amino-5-chlorobenzylalcohol (5.02 g) and acetic acid (4 ml) in toluene (200 ml) were heatedunder reflux using a Dean-Stark trap for 1.5 h. The solvent wasevaporated under reduced pressure to ˜100 ml, tetrahydrofuran (100 ml)added followed by sodium cyanoborohydride (6.3 g). Acetic acid (3 ml)was added dropwise to this mixture which was stirred at room temperaturefor 96 h. The solvents were removed under reduced pressure and theresidue partitioned between ethyl acetate and aqueous sodiumhydrogencarbonate solution. The organics were dried, evaporated underreduced pressure and the residue triturated withdichloromethane/isohexane. Yield 7.5 g.

MS: APCI(+ve) 500(M+1)

(ii) 7-Chloro-1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride

Triphosgene (1.6 g) was added to a stirred solution of the product fromstep (i) (5 g), N,N-diisopropylethylamine (5.2 ml) in tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at room temperature for 16 h,the precipitate filtered and the filtrate evaporated under reducedpressure. Purification was by chromatography eluting with 20% ethylacetate/toluene. The product was dissolved in dichloromethane then asolution of hydrogen chloride in 1,4-dioxane added. After 2 h thesolvent was removed under reduced pressure to yield a solid. Useddirectly.

(iii) Methyl2-({4-[4-(7-chloro-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-3-nitrophenyl}carbonyl)benzoate

Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (0.5 g), the productfrom step (ii) (0.47 g) and triethylamine (0.5 ml) inN,N-dimethylformamide (2.5 ml) were heated at 60° C. overnight. Themixture was evaporated under reduced pressure and the residue purifiedby chromatography eluting with 25% ethyl acetate/toluene. Yield 0.7 g ofa solid.

MS: APCI(+ve) 550(M+1)

1H NMR: δ (DMSO-d6) 8.00-7.97(2H, m), 7.80-7.72(2H, m), 7.70-7.65(1H,m), 7.46(1H, d), 7.40-7.30(4H, m), 5.12(2H, s), 4.20-4.10(1H, m),3.64(3H, s), 3.49(2H, br d), 3.26(2H, br t), 2.70-2.60(2H, m),1.97-1.91(2H, m)

MP: 90-2° C.

EXAMPLES 8-114

(i)3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzoicacid

A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride (1.0 g), 1,1-dimethylethyl 4-chloro-3-nitrobenzoate (0.95g) and triethylamine (0.8 g) in N,N-dimethylformamide (10 ml) wasstirred at room temperature overnight. The mixture was partitionedbetween ethyl acetate and water. The organic layer was dried, andevaporated under reduced pressure. Purification was by chromatographyeluting with 1:2 ethyl acetate-isohexane. The residue was dissolved informic acid (5 ml) stirred overnight at room temperature, heated at 55°C. for 2 h, then evaporated under reduced pressure. The residue wastriturated with ether, yield 0.85 g as a solid.

MS: APCI(+ve) 398(M+1)

(ii) Examples 8-114

Carbonyldiimidazole (0.2 g) was added to a solution of the product fromstep (i) (0.4 g) in N,N-dimethylformamide (25 ml) and stirred at roomtemperature for 2.5 h. The activated acid (0.1 ml) the appropriate amine(5 equivalents) and triethylamine (5 equivalents) in1-methyl-2-pyrrolidinone (0.1 ml) were left at room temperature for 24h. The reaction mixture was evaporated to dryness and the residuedissolved in dimethylsulphoxide (0.4 ml).

EXAMPLE 8N-(1,1-Dimethylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 453(M+1)

EXAMPLE 9N-[(1R)-2-Hydroxy-1-(phenylmethyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 531(M+1)

EXAMPLE 10 Methyl2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate

MS: APCI(+ve) 483(M+1)

EXAMPLE 113-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide

MS: APCI(+ve) 481(M+1)

EXAMPLE 12N-[2-(4-Aminophenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 516(M+1)

EXAMPLE 133-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2,2,2-trifluoroethyl)benzamide

MS: APCI(+ve) 479(M+1)

EXAMPLE 14 Ethyl(2S)-3-methyl-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]butanoate

MS: APCI(+ve) 525(M+1)

EXAMPLE 15 Methyl3-hydroxy-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate

MS: APCI(+ve) 499(M+1)

EXAMPLE 16N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 533(M+1)

EXAMPLE 173-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-phenylethyl)benzamide

MS: APCI(+ve) 501(M+1)

EXAMPLE 18N-[(4-Aminophenyl)methyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 502(M+1)

EXAMPLE 193-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-thien-2-ylethyl)benzamide

MS: APCI(+ve) 507(M+1)

EXAMPLE 20N-[3-(Dimethylamino)-2,2-dimethylpropyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 510(M+1)

EXAMPLE 21N-{[2,4-Bis(methyloxy)phenyl]methyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 547(M+1)

EXAMPLE 22N-Bicyclo[2.2.1]hept-2-yl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 491(M+1)

EXAMPLE 23N-(2-Fluoroethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 443 (M+1)

EXAMPLE 243-Nitro-N-[(3-nitrophenyl)methyl]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 532(M+1)

EXAMPLE 25N-[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 531(M+1)

EXAMPLE 263-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-{[3,4,5-tris(methyloxy)phenyl]methyl}benzamide

MS: APCI(+ve) 577(M+1)

EXAMPLE 273-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-phenylcyclopropyl)benzamide

MS: APCI(+ve) 513(M+1)

EXAMPLE 28N-[2-Hydroxy-1-(hydroxymethyl)-1-methylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 485(M+1)

EXAMPLE 29N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 506(M+1)

EXAMPLE 303-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-piperidin-1-ylethyl)benzamide

MS: APCI(+ve) 508(M+1)

EXAMPLE 31N-(1,3-Dimethylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 481(M+1)

EXAMPLE 32N-(1-Methylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 467(M+1)

EXAMPLE 33N-(1-Methylhexyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 495(M+1)

EXAMPLE 34N-(3-Methylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 467(M+1)

EXAMPLE 35N-[(2-Aminophenyl)methyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 502(M+1)

EXAMPLE 36N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 471(M+1)

EXAMPLE 37N-[2-(Ethylthio)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 485(M+1)

EXAMPLE 38N-[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 497(M+1)

EXAMPLE 39N-(4-Methylcyclohexyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 493(M+1)

EXAMPLE 40N-{2-Hydroxy-1-[(methyloxy)methyl]-2-phenylethyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 561(M+1)

EXAMPLE 41N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 425(M+1)

EXAMPLE 42N-Cyclopropyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 437(M+1)

EXAMPLE 433-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamiide

MS: APCI(+ve) 487(M+1)

EXAMPLE 44N-(1-Methylpropyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 453(M+1)

EXAMPLE 45 1,1-Dimethylethyl2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)anino]ethylcarbamate

MS: APCI(+ve) 440(M+1-Boc)

EXAMPLE 46N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 533(M+1)

EXAMPLE 47N-{[4-(Methyloxy)phenyl]methyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 517(M+1)

EXAMPLE 48N-[2-(1H-Imidazol-4-yl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 491(M+1)

EXAMPLE 49N-[(1S)-1-(Hydroxymethyl)propyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 469(M+1)

EXAMPLE 503-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-[1-(phenylmethyl)piperidin-4-yl]benzamide

MS: APCI(+ve) 570(M+1)

EXAMPLE 51N-[(1R)-1-(Hydroxymethyl)propyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 469(M+1)

EXAMPLE 52N-(4-Hydroxybutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 469(M+1)

EXAMPLE 533-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-tricyclo[3.3.1.1˜3,7˜]dec-1-ylbenzamide

MS: APCI(+ve) 531(M+1)

EXAMPLE 54N-[(1S,2S)-2-Hydroxycyclohexyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 495(M+1)

EXAMPLE 55N-(2-Hydroxy-1-methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 455(M+1)

EXAMPLE 56N-{2-[(2-Hydroxyethyl)oxy]ethyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 485(M+1)

EXAMPLE 57N-[1-(Hydroxymethyl)butyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 483(M+1)

EXAMPLE 58N-(2-Amino-2-oxoethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 454(M+1)

EXAMPLE 59N-[1-(4-Fluorophenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 519(M+1)

EXAMPLE 603-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(3-phenylpropyl)benzamide

MS: APCI(+ve) 515(M+1)

EXAMPLE 61N-[(1S,2R)-2-Hydroxycyclohexyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 495(M+1)

EXAMPLE 62 Ethyl3-hydroxy-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate

MS: APCI(+ve) 513(M+1)

EXAMPLE 63N-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 531(M+1)

EXAMPLE 641-{1-[4-(Morpholin-4-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 467(M+1)

EXAMPLE 65N,N-Dimethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 425(M+1)

EXAMPLE 66N,N-Bis(2-hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 485 (M+1)

EXAMPLE 67N-(2-Hydroxyethyl)-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 455(M+1)

EXAMPLE 68N-(2-Hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide

MS: APCI(+ve) 531 (M+1)

EXAMPLE 691-(1-{2-Nitro-4-[(4-phenylpiperazin-1-yl)carbonyl]phenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 542(M+1)

EXAMPLE 70N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 545(M+1)

EXAMPLE 71N-Ethyl-N-(2-hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 469(M+1)

EXAMPLE 721-[1-(4-{[4-(4-Fluorophenyl)piperazin-1-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 560(M+1)

EXAMPLE 731-{1-[4-(Azepan-1-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 479(M+1)

EXAMPLE 74N,N-Diethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 453(M+1)

EXAMPLE 75N-[2-(Dimethylamino)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide

MS: APCI(+ve) 558(M+1)

EXAMPLE 76N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide

MS: APCI(+ve) 515(M+1)

EXAMPLE 77N-Butyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide

MS: APCI(+ve) 543(M+1)

EXAMPLE 781-{1-[2-Nitro-4-(piperidin-1-ylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 465(M+1)

EXAMPLE 79 Ethyl[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)(phenylmethyl)amino]acetate

MS: APCI(+ve) 573(M+1)

EXAMPLE 80N-(2-Hydroxyethyl)-N-(1-methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 483(M+1)

EXAMPLE 811-(1-{2-Nitro-4-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 543(M+1)

EXAMPLE 821-{1-[2-Nitro-4-(pyrrolidin-1-ylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 451(M+1)

EXAMPLE 83N-(2-Hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-pentylbenzamide

MS: APCI(+ve) 511(M+1)

EXAMPLE 84N-[2-(Diethylamino)ethyl]-N-ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 524(M+1)

EXAMPLE 85N-Ethyl-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4n)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 439(M+1)

EXAMPLE 86(2S)-1-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)pyrrolidine-2-carboxamide

MS: APCI(+ve) 494(M+1)

EXAMPLE 87N-(2-Cyanoethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-(phenylmethyl)benzamide

MS: APCI(+ve) 540(M+1)

EXAMPLE 881-(1-{4-[(3,5-Dimethylpiperidin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 493(M+1)

EXAMPLE 891-[1-(4-{[(2R,6S)-2,6-Dimethylmorpholin4-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 495(M+1)

EXAMPLE 901-{1-[4-({4-[2-(Methyloxy)phenyl]piperazin-1-yl}carbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 572(M+1)

EXAMPLE 911-{1-[2-Nitro-4-(thiomorpholin4-ylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 483(M+1)

EXAMPLE 92

MS: APCI(+ve) 548(M+1)

EXAMPLE 931-(1-{4-[(4-{2-[(2-Hydroxyethyl)oxy]ethyl}piperazin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 554(M+1)

EXAMPLE 94N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(pyridin-4-ylmethyl)benzamide

MS: APCI(+ve) 516(M+1)

EXAMPLE 95N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-prop-2-ynylbenzamide

MS: APCI(+ve) 449(M+1)

EXAMPLE 961-(1-{4-[(4-Acetylpiperazin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 508(M+1)

EXAMPLE 971-[1-(4-{[2-(Hydroxymethyl)piperidin-1-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 495(M+1)

EXAMPLE 984-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperazine-1-carbaldehyde

MS: APCI(+ve) 494(M+1)

EXAMPLE 99N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide

MS: APCI(+ve) 501(M+1)

EXAMPLE 100 Ethyl4-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperazine-1-carboxylate

MS: APCI(+ve) 538(M+1)

EXAMPLE 101 Ethyl1-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-4-carboxylate

MS: APCI(+ve) 537(M+1)

EXAMPLE 1021-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-3-carboxamide

MS: APCI(+ve) 508(M+1)

EXAMPLE 1031-(1-{4-[(4-Methylpiperazin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 480(M+1)

EXAMPLE 1041-{1-[4-(2,5-Dihydro-1H-pyrrol-1-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 449(M+1)

EXAMPLE 105N-Ethyl-N-(2-methylprop-2-enyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 479(M+1)

EXAMPLE 106N,N-Bis(cyanomethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 475(M+1)

EXAMPLE 107N-Butyl-N-(cyanomethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 492(M+1)

EXAMPLE 108N,N-Bis(2-hydroxypropyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 513(M+1)

EXAMPLE 1091-(1-{4-[(4-Hydroxypiperidin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 481(M+1)

EXAMPLE 1101-(1-{4-[(2,5-Dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

MS: APCI(+ve) 477(M+1)

EXAMPLE 111N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-propylbenzamide

MS: APCI(+ve) 453(M+1)

EXAMPLE 112N-(2-Amino-2-oxoethyl)-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 468(M+1)

EXAMPLE 113N,N-Diethyl-1-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-3-carboxamide

MS: APCI(+ve) 564(M+1)

EXAMPLE 114N-Cyclohexyl-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 493(M+1)

EXAMPLE 115N-(1-Methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridazine-3-carboxamide

(i) 6-Chloro-N-(1-methylethyl)pyridazine-3caroxamide

A solution of 6-chloro-3-pyridazinecarboxylic acid (0.25 g) andcarbonyldiimidazole (0.282 g) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 1 h. Isopropylamine (0.162 ml) wasadded, the mixture stirred for 3 h then partitioned between ethylacetate and water. The organic layer was washed with water, dried, andevaporated under reduced pressure. Yield 0.284 g.

1H NMR: δ (DMSO-d6) 9.02(1H, d), 8.22(1H, d), 8.09(1H, d), 4.22-4.13(1H,m), 1.21(6H, d)

(ii)N-(1-Methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridazine-3-carboxamide

1-Piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.38g), the product from step (i) (0.28 g) and N,N-diisopropylethylamine(0.73 ml) in I-methyl-2-pyrrolidinone (6 ml) was heated at 100° C. for 8h. The mixture was partitioned between ethyl acetate and water, theorganic layer washed with water, dried, and evaporated under reducedpressure. Purification was by chromatography eluting with 80% ethylacetate/isohexane to yield 0.225 g of a solid.

MS: APCI(+ve) 396(M+1)

1H NMR: δ (DMSO-d6) 8.51(1H, d), 7.84(1H, d), 7.45-7.35(3H, m), 7.30(1H,d), 7.13(1H, t), 5.14(2H, s), 4.64(2H, br d), 4.31-4.26(1H, m),4.18-4.09(1H, m), 3.20(2H, t), 2.50-2.44(2H, m), 1.91(2H, br d),1.19(6H, d)

MP: 120° C.

EXAMPLE 116N-[2-(Methyloxy)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was prepared from the product of example 8 step (i)and 2-methoxyethylamine (0.5 ml) using the method of example 115 step(i). Yield 0.065 g.

MS: APCI(+ve) 455(M+1)

1H NMR: δ (CDCl₃) 8.22(1H, dd), 7.92(1H, dd), 7.37(1H, t), 7.20-7.09(4H,m), 6.46(1H,br s), 5.10(2H, s), 4.25-4.17(1H, m), 3.68-3.47(6H, m),3.40(3H, s), 3.15(2H, t), 2.93-2.79(2H, m), 1.95(2H, d)

MP: 192-3° C.

EXAMPLE 117N-(1-Methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

(i) 6-Chloro-N-(1-methylethyl)pyridine-3-carboxamide

The product was prepared from 6-chloro-nicotinic acid (1.0 g),carbonyldiimidazole (0.8 g) and isopropylamine (0.6 ml) using the methodof example 115 step (i). Yield 0.75 g.

MS: APCI(+ve) 199(M+1)

(ii)N-(1-Methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of step (i) (0.4 g) and1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.5g) using the method of example 115 step (ii). Yield 0.22 g.

1H NMR: δ (DMSO-d6) 8.59(1H, d), 7.97-7.94(2H, m), 7.41-7.28(3H, m),7.12(1H, t), 6.90(1H, d), 5.13(2H, s), 4.56(2H, br d), 4.25-4.18(1H, m),4.12-4.00(1H, m), 3.06(2H, t), 2.50-2.38(2H, m), 1.85(2H, br d),1.15(6H, d)

MP: >230° C.

EXAMPLE 1185-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

(i) 5,6-Dichloro-N-(1-methylethyl)pyridine-3-carboxamide

The product was prepared from 5,6-dichloro-nicotinic acid (0.86 g),carbonyldiimidazole (0.8 g) and isopropylamine (0.52 ml) using themethod of example 115 step (i). Yield 0.69 g.

MS: APCI(+ve) 199(M+1)

(ii)5-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of step (i) (0.3 g) and1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.35g) using the method of example 115 step (ii). Yield 0.187 g.

MS: APCI(+ve) 429(M+1)

1H NMR: δ (DMSO-d6) 8.64(1H, d), 8.25(1H, d), 8.18(1H, d), 7.40(1H, t),7.33-7.30(2H, m), 7.12(1H, t), 5.15(2H, s), 4.18-4.02(4H, m), 3.06(2H,t), 2.71-2.60(2H, br d), 1.16(6H, d)

MP: 216° C.

EXAMPLE 119N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzenesulfonamide

(i) 4-Chloro-N-(1-methylethyl)-3-nitrobenzenesulfonamide

4-Chloro-3-nitrobenzenesulfonyl chloride (2 g) and isopropylamine (2.1ml) in dichloromethane (30 ml) was stirred at room temperature for 2 h.The mixture was washed with water, 2M hydrochloric acid, water, driedand evaporated under reduced pressure. Yield 2.2 g.

1H NMR: δ (DMSO-d6) 8.45(1H, d), 8.09-7.98(3H, m), 3.39-3.31(1H,septet), 0.99(6H, d)

(ii)N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzenesulfonamide

The title compound was prepared from the product of step (i) (0.14 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(0.1 g) using the method of example 115 step (ii). Yield 0.037 g.

MS: APCI(+ve) 475(M+1)

1H NMR: δ (DMSO-d6) 8.17(1H, d), 7.86(1H, dd), 7.63(1H, d), 7.48(1H, d),7.40(1H, t), 7.34-7.30(2H, m), 7.13(1H, t), 5.15(2H, s), 4.19-4.13(1H,m), 3.46(2H, d), 3.32-3.20(3H, m), 2.67-2.59(2H, m), 1.88(2H, d),0.98(6H, d)

MP: 168° C.

EXAMPLE 1201-[1-(4-Amino-2-chlorophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

(i)1-[1-(2-Chloro-4-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

The product was prepared from1-piperidin-4yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (1.5g) and 3-chloro-4-fluoronitrobenzene (1.23 g) using the method ofexample 115 step (ii). Yield 1.37 g.

MS: APCI(+ve) 388(M+1)

(ii)1-[1-(4-Amino-2-chlorophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

Iron powder (1.5 g) was added to a solution of the product from step (i)(1.37 g) in acetic acid (50 ml) and tetrahydrofuran (20 ml). Afterstirring at room temperature for 5 h, the mixture was filtered throughcelite, the solvent removed under reduced pressure and the residuepartitioned between ethyl acetate and aqueous sodium hydrogencarbonatesolution. The organic layer was washed with water, dried and evaporatedunder reduced pressure. Purification was by chromatography eluting with50% ethyl acetate/isohexane. Yield 1.05 g.

MS: APCI(+ve) 358(M+1)

1H NMR: δ (DMSO-d6) 7.40(1H, t), 7.29(2H, m), 7.12(1H, t), 6.92(1H, d),6.64(1H, d), 6.49(1H, dd), 5.14(2H, s), 5.03(2H, s), 3.98-3.92(1H, m),3.14(2H, d), 2.7-2.62(4H, m), 1.83(2H, br d)

MP: 158° C.

EXAMPLE 1213-Cyano-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

(i) Methyl 4-chloro-3-cyanobenzoate

A solution of sodium nitrite (1.28 g) in water (8 ml) was added over 10min to a mixture of methyl 3-amino-4-chlorobenzoate (4.0 g) in water (40ml) and concentrated hydrochloric acid (5 ml) at 0° C. After 30 min themixture was neutralised with aqueous sodium hydroxide solution to pH˜7then added portionwise to a solution of copper cyanide (prepared fromsodium cyanide (2.87 g) and copper(I) chloride (2.23 g) in water (40ml)) at 0° C. The mixture was stirred at room temperature for 2 h thenpartitioned between ethyl acetate and water. The organics were washedwith water, dried and evaporated under reduced pressure. The residue wastriturated with 20% ethyl acetate/isohexane to yield a solid (1.55 g).

1H NMR: δ (CDCl₃) 8.34(1H, d), 8.21-8.17(1H, m), 7.62(1H, dd), 3.96(3H,s)

(ii) 4-Chloro-3-cyanobenzoic acid

A solution of the product from step (i) (1.5 g) and lithium hydroxidehydrate (0.84 g) in a mixture of (1:1)water and tetrahydrofuran (40 ml)was stirred at room temperature for 2 h. The tetrahydrofuran was removedunder reduced pressure and the residue partitioned between diethyl etherand water. The aqueous layer was acidified with 2M hydrochloric acidthen extracted with ethyl acetate. The organic layer was dried andevaporated under reduced pressure. Yield 1.3 g.

1H NMR: δ (CDCl₃) 8.42(1H, d), 8.28-8.24(1H, m), 7.67(1H, dd)

(iii) 4-Chloro-3-cyano-N-(1-methylethyl)benzamide

The above compound was prepared from the product of step (ii) (0.6 g),carbonyldiimidazole (0.59 g) and isopropylamine (0.51 ml) using themethod of example 115 step (i). Yield 0.68 g.

1H NMR: δ (CDCl₃) 8.06(1H, d), 7.96-7.92(1H, m), 7.59(1H, d), 5.96(1H,br s), 4.28(1H, septet), 1.29(6H, d)

(iv)3-Cyano-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was prepared from the product of step (iii) (0.29 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(0.3 g) using the method of example 115 step (ii). Yield 0.073 g.

MS: APCI(+ve) 419(M+1)

1H NMR: δ (DMSO-d6) 8.21(1H, d), 8.18(1H, d), 8.03(1H, dd), 7.40(1H, t),7.34-7.30(2H, m), 7.22(1H, d), 7.13(1H, t), 5.16(2H, s), 4.16-4.04(2H,m), 3.81(2H, br d), 3.14(2H, t), 2.75-2.65(2H, m), 1.93(2H, br d),1.16(6H, d)

MP: 200° C.

EXAMPLE 122N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-2-methylpropanamide

Isobutyryl chloride (0.017 ml) was added to a stirred solution of theproduct from example 120 step (ii) (0.05 g) and triethylamine (0.07 ml)in dichloromethane (1 ml) at room temperature. After 2 h the mixture waspartitioned between ethyl acetate and water, the organics separated,washed with water, dried, and evaporated under reduced pressure.Trituration with ether gave a solid, yield 0.048 g.

MS: APCI(+ve) 428(M+1)

1H NMR: δ (DMSO-d6) 9.86(1H, s), 7.79(1H, d), 7.46(1H, dd),7.42-7.38(1H, m), 7.31-7.29(2H, m), 7.14-7.10(2H, m), 5.15(2H, s),4.04-3.98(1H, m), 3.33-2.84(2H, m), 2.82(2H, t), 2.75-2.65(2H, m),2.59-2.50(1H, m), 1.87(2H, br d), 1.09(6H, d)

MP: 228° C.

EXAMPLE 123N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}propane-2-sulfonamide

Isopropylsulphonyl chloride (0.03 ml) was added to a stirred solution ofthe product from example 120 step (ii) (0.05 g), pyridine (0.1 ml) inacetonitrile (0.9 ml) at room temperature. The mixture was stirredovernight, partitioned between ethyl acetate and water, the organicsseparated, washed with water, dried, and evaporated under reducedpressure. Purification was by chromatography eluting with 40% ethylacetate/isohexane. Yield 0.015 g.

MS: APCI(+ve) 464(M+1)

1H NMR: δ (DMSO-d6) 9.76(1H, s), 7.40(1H, t), 7.31-7.27(3H, m),7.19-7.10(3H, m), 5.15(2H, s), 4.04-3.98(1H, m), 3.30(2H, br d),3.25-3.18(1H, m), 2.82(2H, t), 2.74-2.65(2H, m), 1.87(2H, br d),1.24(6H, d)

MP: 175° C.

EXAMPLE 124N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-cyanocyclopropanecarboxamide

The title compound was prepared from the product of example 120 step(ii) (0.05 g), carbonyldiimidazole (0.025 g) and 1-cyano-1-cyclopropanecarboxylic acid (0.019 g) using the method of example 115 step (i).Yield 0.003 g.

MS: APCI(+ve) 451 (M+1)

1H NMR: δ (DMSO-d6) 10.02(1H, s), 7.70(1H, d), 7.52-7.48(1H, m),7.40(1H, t), 7.30(2H, t), 7.17-7.10(2H, m), 5.15(2H, s), 4.05-3.99(1H,m), 3.32(2H, d), 2.83(2H, t), 2.74-2.67(2H, m), 1.88(2H, d), 1.67(4H, s)

EXAMPLE 125(2S)-N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-methylpyrrolidine-2-carboxamide

A mixture of the product from example 120 step (ii) (0.1 g),N-methyl-L-proline (0.044 g), N,N-diisopropylethylamine (0.17 ml),1-hydroxybenzotriazole (0.043 g),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(0.103 g) in N,N-dimethylformamide (3 ml) were stirred at roomtemperature overnight then partitioned between ethyl acetate and water.The organic layer was washed with water, dried and evaporated underreduced pressure. Purification was by chromatography eluting with 4%methanol/dichloromethane. Yield 0.038 g.

MS: APCI(+ve) 469(M+1)

1H NMR: δ (DMSO-d6) 9.73(1H, s), 7.88(1H, d), 7.59(1H, dd), 7.38(1H, t),7.30(2H, d), 7.14-7.10(2H, m), 5.15(2H, s), 4.04-3.98(1H, m), 3.30(2H,d), 3.12-3.08(1H, m), 2.90-2.67(5H, m), 2.35-2.29(1H, m), 2.33(3H, s),2.18-2.09(1H, m) 1.87(2H, br d), 1.82-1.75(3H, m)

MP: 155° C.

EXAMPLE 1265-Chloro-N-(1-methylethyl)-6-[4-(4-methyl-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

(i) 1,1-Dimethylethyl4-(4-methyl-2-oxo-2H-3,1-benzoxazin-1(4H)-yi)piperidine-1-carboxylate

Acetic acid (1 ml) was added dropwise to a solution ofN-tert-butoxycarbonyl-4-piperidone (9.4 g), 1-(2-amino-phenyl)-ethanol(4.3 g) and sodium cyanoborohydride (10 g) in dichloromethane and themixture stirred at room temperature overnight. The mixture waspartitioned between ethyl acetate and water, the organics separated andwashed with aqueous sodium hydrogencarbonate solution, water, dried, andevaporated under reduced pressure. The crude product was dissolved intetrahydrofuran (100 ml) and N,N-diisopropylethylamine (23 ml), cooledto 0° C., then triphosgene (4.3 g) added. The mixture was warmed to roomtemperature and stirred overnight. The mixture was partitioned betweenethyl acetate and water, the organics washed with water, dried andevaporated under reduced pressure. Purification was by chromatographyeluting with 20% ethyl acetate/isohexane. Yield 1.4 g.

MS: APCI(+ve) 247(M+1-Boc)

(ii) 4-Methyl-1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride

4M Hydrogen chloride in 1,4-dioxane (20 ml) was added to a solution ofthe product from step (i) (1.4 g) in 1,4-dioxane (20 ml) and the mixturestirred at room temperature overnight. The solvent was removed underreduced pressure and the residue triturated with ether. Yield 1.0 g.

MS: APCI(+ve) 247(M+1)

(iii)5-Chloro-N-(1-methylethyl)-6-[4-(4-methyl-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of step (ii) (0.36 g)and the product from example 117 step (i) (0.466 g) using the method ofexample 115 step (ii). Yield 0.112 g

MS: APCI(+ve) 443(M+1)

1H NMR: δ (DMSO-d6) 8.64(1H, d), 8.25(1H, d), 8.18(1H, d), 7.42-7.38(1H,m), 7.34-7.27(2H, m), 7.16-7.12(1H, m), 5.36(1H, q), 4.18-4.05(4H, m),3.09-3.02(2H, m), 2.72-2.61(2H, m), 1.89(2H, br d), 1.57(3H,d), 1.16(6H,d)

EXAMPLES 127±-5-Chloro-N-(1-methylethyl)-6-[(cis)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamidehydrochloride

EXAMPLE 128±-5-Chloro-N-(1-methylethyl)-6-[(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamidehydrochloride

(i) 1,1-Dimethylethyl4-{[2-(hydroxymethyl)phenyl]amino}-3-methylpiperidine-1-carboxylate

The product was prepared fromN-tert-butoxycarbonyl-3-methyl-4-piperidone (4.3 g) and 2-amino-benzylalcohol (2.59 g) using the method of example 7 step (i). Yield 6.3 g asa mixture of diastereoisomers.

MS: APCI(+ve) 320(M+1)

(ii) ±-1,1-Dimethylethyl(cis)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate

±-1,1-Dimethylethyl(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate

The above compounds were prepared from the product of step (i) (6.3 g)using the method of example 7 step (ii). Cis and trans diastereoisomerswere separated (relative stereochemistry).

±-1,1-Dimethylethyl(cis)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate,yield 0.24 g MS: APCI(+ve) 247(M+1)

±-1,1-Dimethylethyl(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate,yield 0.68 g MS: APCI(+ve) 247(M+1)

(iii)±-5-Chloro-N-(1-methylethyl)-6-1(cis)-3-methyl-4-(2-oxo-2-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxaniidehydrochloride

±-1,1-Dimethylethyl(cis)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate(0.24 g) was dissolved in 4M hydrogen chloride in 1,4-dioxane (5 ml)stirred at room temperature for 4 h, then evaporated under reducedpressure. The product was dissolved in 1-methyl 2-pyrrolidinone (10 ml),N,N-diisopropylethylamine (0.5 ml) and the product from example 117 step(i) (0.23 g) added. The mixture was heated at 100° C. for 12 h,partitioned between ethyl acetate and water, the organics separated,dried and evaporated under reduced pressure. Purification was bychromatography eluting with 30-40% ethyl acetate/isohexane. Thehydrochloride salt was made from ethereal hydrogen chloride. Yield 0.07g.

MS: APCI(+ve) 443(M+1)

1H NMR: δ (DMSO-d6) 8.64(1H, d), 8.27(1H, d), 8.19(1H, d), 7.41-7.30(3H,m), 7.12(1H, t), 6.12(2H, br s), 5.22-5.14(2H, m), 4.12-3.99(3H, m),3.77(1H, br s), 3.13(1H, br t), 2.86(1H, br s), 2.75-2.50(2H, m),1.94(1H, br d), 1.16(6H, d), 0.87(3H, d)

MP: 215° C.

±-5-chloro-N-(1-methylethyl)-6-[(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamidehydrochloride

The titled compound was prepared from ±-1,1-dimethylethyl(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidine-1-carboxylate(0.68 g) using the same method as step (iii). Yield 0.219 g.

MS: APCI(+ve) 443(M+1)

1H NMR: δ (DMSO-d6) 8.63(1H, s), 8.25(1H, d), 8.17(1H, s), 7.40-7.29(2H,m), 7.28(1H, d), 7.12(1H, t), 6.04(2H, br s), 5.21-5.13(2H, m),4.29-4.24(1H, m), 4.12-3.91(3H, m), 3.30(1H, dd), 3.18-3.02(2H, m),2.56-2.54(1H, m), 1.87(1H, br d), 1.16(6H, d), 1.09(3H, d)

MP: 195° C.

EXAMPLES 129-144

(i)2-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxylicacid

The title compound was prepared from1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.70g) and 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (1.8 g)using the method of example 115 step (ii). Yield 1.1 g.

MS: APCI(+ve) 423(M+1)

(ii) Examples 129-144

Oxalyl chloride (0.1 ul) was added to a solution of the product fromstep (i) (0.27 g) in dichloromethane (10 ml) and stirred at roomtemperature for 3 h. The solvent was removed under reduced pressure andthe residue dissolved in 1-methyl-2-pyrrolidinone. An aliquot of thesolution of the acid chloride (0.1 ml), the appropriate amine (2equivalents) and triethylamine (5 equivalents) in1-methyl-2-pyrrolidinone (0.03 ml) were left at room temperature for 24h. The reaction mixture was evaporated to dryness and the residuedissolved in dimethylsulphoxide (0.4 ml).

EXAMPLE 1292-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 505(M+1)

EXAMPLE 1302-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 488(M+1)

EXAMPLE 1312-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1H-pyrazol-3-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 487(M+1)

EXAMPLE 132N-(4-Hydroxycyclohexyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 519(M+1)

EXAMPLE 133N-[1-(Hydroxymethyl)propyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 493(M+1)

EXAMPLE 134N-(3-Hydroxy-2,2-dimethylpropyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 507 (M+1)

EXAMPLE 1352-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(tetrahydrofuran-2-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 505(M+1)

EXAMPLE 136N-Cyclobutyl-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 475(M+1)

EXAMPLE 137N-Cyclopentyl-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 489(M+1)

EXAMPLE 138N-[2-(1H-Imidazol-4-yl)ethyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 515(M+1)

EXAMPLE 139N-(1-Ethynylcyclohexyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimdine-5-carboxamide

MS: APCI(+ve) 527(M+1)

EXAMPLE 140N-[(1R)-1-(Hydroxymethyl)-2-methylpropyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 507(M+1)

EXAMPLE 141N-(2-Hydroxy-1,1-dimethylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 493(M+1)

EXAMPLE 142N-(1,1-Diethylprop-2-ynyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 515(M+1)

EXAMPLE 143N-(2-Hydroxy-1-methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 479(M+1)

EXAMPLE 144N-[1-Methyl-2-(methyloxy)ethyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide

MS: APCI(+ve) 493(M+1)

EXAMPLE 145N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyrimidine-5-carboxaamide

(i) N-(1-Methylethyl)-2-(methylthio)pyrimidine-5-carboxamide

The product was prepared fromN-(1-methylethyl)-2-(methylthio)pyrimidine-5-carboxylic acid (Acta ChemScand., Ser.B (1986), B40(9), 764-767.) (0.78 g), carbonyldiimidazole(0.82 g) and isopropylaniine (0.3 g) using the method of example 115step (i). Yield 0.66 g.

MS: APCI(+ve) 212 (M+1)

(ii)N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyrimidine-5-carboxamide

The product from step (i) (0.66 g) was dissolved in chloroform (50 ml)and to this solution was added 3-chloroperoxybenzoic acid (2.02 g). Themixture was stirred for 1 h at room temperature before being washed withan aqueous solution of sodium metabisulphite followed by aqueous sodiumbicarbonate. The organic layer was dried and evaporated under reducedpressure. The residue was dissolved in 1-methyl-2-pyrrolidinone (4 ml)and this solution treated with N,N-diisopropylethylamine (0.5 ml)followed by 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride (0.2 g) before being heated at 60° C. for 2 h. The mixturewas partitioned between water and ethyl acetate, the organic layerwashed with water, dried and evaporated under reduced pressure.Purification was by chromatography eluting with ethyl acetate/isohexane(2/1). Yield 0.03 g as a solid.

MS: APCI(+ve) 396 (M+1)

1H NMR: δ (DMSO-d6) 8.77(2H, s), 8.07(1H, d), 7.41-7.29(3H, m), 7.12(1H,t), 5.14(2H, s), 4.88(2H, d), 4.28-4.22(1H, m), 4.11-4.02(1H, m),3.12(2H, t), 2.45-2.3(2H, m), 1.89(2H, d), 1.16(6H, d)

MP: 236-239° C.

EXAMPLE 146N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-1,3-thiazole4-carboxamide

(i) 2-Bromo-N-(1-methylethyl)-1,3-thiazole4-carboxamide

The product was prepared from2-bromo-N-(1-methylethyl)-1,3-thiazole-4-carboxylic acid (WO 9848799)(0.77 g), carbonyldiimidazole (0.66 g) and isopropylamine (0.24 g) usingthe method of example 115 step (i). Yield 0.82 g.

1H NMR: δ (DMSO-d6) 8.25(1H, s), 8.24-8.18(1H, m), 4.14-4.02(1H, m),1.16(6H, d)

(ii)N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-1,3-thiazole4-carboxamide

The title compound was prepared from the product of step (i) (0.16 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(0.15 g) using the method of example 115 step (ii). Yield 0.04 g.

MS: APCI(+ve) 401 (M+1)

1H NMR: δ (DMSO-d6) 7.68(1H, d), 7.43-7.29(4H, m), 7.13(1H, t), 5.16(2H,s), 4.22-3.99(4H, m), 3.29-3.18(2H, m), 2.64-2.49(2H, m), 1.91(2H, d),1.16(6H, d)

MP: 214-215° C.

EXAMPLE 147N-(1-Methylethyl)-3-(methylsulfonyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

4-Fluoro-N-(1-methylethyl)-3-(methylsulfonyl)benzoic acid (J.Med.Chem(1997), 40(13), 2017-2034) (0.45 g) was reacted with carbonyldiimidazole(0.37 g) and isopropylamine (0.25 g) using the method of example 115step (i) to yield the corresponding amide. Yield 0.50 g.

A solution of this amide (0.50 g) in 1-methyl-2-pyrrolidinone (10 ml)was treated with 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-onehydrochloride (0.40 g) followed by N,N-diisopropylethylamine (0.73 g)and the resultant mixture heated at 100° C. for 14 h. The mixture wasthen partitioned between water and ethyl acetate, the organic layerwashed with water, dried and evaporated under reduced pressure. Theresultant solid was washed with ethyl acetate (10 ml) followed byethanol (1 ml) to yield the desired product as a solid (0.13 g).

MS: APCI(+ve) 472 (M+1)

1H NMR: δ (DMSO-d6) 8.47(1H, d), 8.38(1H, d), 8.16(1H, d), 7.63(1H, d),7.42(1H, t), 7.32-7.29(2H, m), 7.13(1H, t), 5.16(2H, s), 4.14-4.05(2H,m), 3.49(3H, s), 3.32-3.29(2H, m), 3.03(2H, t), 2.83-2.76(2H, m),1.91-1.88(2H, m), 1.17(6H, d)

MP: 240-242° C.

EXAMPLE 148N-[(1R)-1-(Aminocarbonyl)-2-methylpropyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

(i)5-Chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxylicacid

The title compound was prepared from 5,6-dichloronicotinic acid (2.2 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(3.0 g) using the method of example 115 step (ii). Yield 0.037 g

MS: APCI(+ve) 388 (M+1)

(ii)N-[(1R)-1-(Aminocarbonyl)-2-methylpropyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The product of step (i) (0.14 g) was dissolved in1-methyl-2-pyrrolidinone (4 ml) and to this solution was addedcarbonyldiimidazole (0.064 g) the mixture was stirred at roomtemperature for 1 h and then treated with D-valinamide hydrochloride(0.11 g) and N,N-diisopropylethylamine (0.10 g). After stirring for 18 hat room temperature the mixture was partitioned between aqueous sodiumbicarbonate and ethyl acetate, the organic layer was washed with water,dried and evaporated under reduced pressure. The resultant solid waswashed with ethyl acetate to yield 0.06 g of product.

MS: APCI(+ve) 486 (M+1)

1H NMR: δ (DMSO-d6) 8.68(1H, d), 8.31-8.27(2H, m), 7.46(1H, s),7.42-7.29(3H, m), 7.13(1H, t), 7.06(1H, s), 5.15(2H, s), 4.26(1H, t),4.19-4.04(3H, m), 3.07(2H, t), 2.72-2.60(2H, m), 2.14-2.07(1H, m),1.90(2H, d), 0.94-0.91(6H, m)

MP: 140-143° C.

EXAMPLE 1495-Chloro-N-(2-hydroxy-1-methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 148 step (i)(0.14 g), carbonyldiimidazole (0.064 g) and DL-2-amino-1-propanol (0.05g) using the method of example 115 step (i). Purification was bychromatography eluting with 20% ethyl acetate/isohexane. Yield 0.04 g asa solid.

MS: APCI(+ve) 445 (M+1)

1H NMR: δ (DMSO-d6) 8.64(1H, d), 8.20(1H, d), 8.15(1H, d), 7.42-7.29(3H,m), 7.12(1H, t), 5.15(2H, s), 4.72(1H, t), 4.15-3.98(4H, m),3.48-3.37(2H, m), 3.06(2H, t), 2.73-2.62(2H, m), 1.89(2H, d),1.13-1.09(3H, m)

MP: 125-128° C.

EXAMPLE 1505-Chloro-N-(1,1-dimethylprop-2-ynyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 148 step (i)(0.14 g), carbonyldiimidazole (0.064 g) and 1,1-dimethylpropargylamine(0.06 g) using the method of example 115 step (i). Purification was bychromatography eluting with ethyl acetate/isohexane (2/3). Yield 0.03 gas a solid.

MS: APCI(+ve) 453 (M+1)

1H NMR: δ (DMSO-d6) 8.62(1H, d), 8.29(1H, s), 8.18(1H, d), 7.42-7.29(3H,m), 7.12(1H, t), 5.15(2H, s), 4.19-4.07(3H, m), 3.12(1H, s), 3.07(2H,t), 2.72-2.60(2H, m), 1.90(2H, d), 1.60(6H, s)

MP: 135-138° C.

EXAMPLE 151N-(2-Amino-1-cyano-2-oxoethyl)-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The product of example 148 step (i) (0.14 g) was stirred as a suspensionin dichloromethane (4 ml) and to this mixture was added oxalyl chloride(0.05 g) followed by N,N-dimethylformamide (0.01 g). After stirring for1 h at room temperature the mixture was treated with2-aminocyanoacetanide (0.14 g) 1-methyl-2-pyrrolidinone (3 ml) and thenN,N-diisopropylethylamine (1 ml), stirring was then continued for afurther 18 h at room temperature. The reaction mixture was partitionedbetween aqueous sodium bicarbonate and ethyl acetate, the organic layerwas washed with water, dried and evaporated under reduced pressure.Purification was by chromatography eluting with 25% ethylacetate/isohexane. Yield 0.09 g as a solid.

MS: APCI(+ve) 469 (M+1)

1H NMR: δ (DMSO-d6) 9.63(1H, d), 8.69(1H, d), 8.25(1H, d), 7.83(1H, s),7.68(1H, s), 7.40(1H, t), 7.34-7.30(2H, m), 7.13(1H, t), 5.67(1H, d),5.15(2H, s), 4.17-4.14(3H, m), 3.10(2H, t), 2.69-2.61(2H, m), 1.91(2H,d)

MP: 159-162° C.

EXAMPLE 152N-[(1R)-1-(Aminocarbonyl)-3-methylbutyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 148 step (i)(0.15 g) and (R)-leucinamide hydrochloride (0.07 g) according to themethod of example 115, step (i). Yield 0.05 g as a solid.

MS: APCI(+ve) 500 (M+1)

1H NMR: δ (DMSO-d6) 8.68(1H, d), 8.45(1H, d), 8.27(1H, d), 7.42-7.29(4H,m), 7.12(1H, t), 6.98(1H, s), 5.15(2H, s), 4.44-4.41(1H, m),4.15-4.07(3H, m), 3.07(2H, t), 2.68-2.64(2H, m), 1.90(2H, d),1.70-1.54(3H, m), 0.92-0.86(6H, m)

MP: 139-142° C.

EXAMPLE 153N-[(1S)-1-(Amiocarbonyl)-2-methylpropyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 148 step (i)(0.15 g) and (S)-valinamide hydrochloride (0.08 g) according to themethod of example 115, step (i). Yield 0.03 g as a solid.

MS: APCI(+ve) 486 (M+1)

1H NMR: δ (DMSO-d6) 8.68(1H, t), 8.31-8.28(2H, m), 7.46-7.29(4H, m),7.13(1H, t), 7.06(1H, s), 5.15(2H, s), 4.24-4.00(4H, m), 3.07(2H, t),2.73-2.61(2H, m), 2.14-2.05(1H, m), 1.90(2H, d), 0.94(3H, s), 0.92(3H,s)

EXAMPLE 154N-[(1S)-1-(Aminocarbonyl)-3-methylbutyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 148 step (i)(0.15 g) and (S)-leucinamide hydrochloride (0.07 g) according to themethod of example 115, step (i). Yield 0.04 g as a solid.

MS: APCI(+ve) 500 (M+1)

1H NMR: δ (DMSO-d6) 8.68(1H, d), 8.45(1H, d), 8.27(1H, d), 7.42-7.29(4H,m), 7.13(1H, t), 6.98(1H, s), 5.15(2H, s), 4.44-4.42(1H, m),4.15-4.04(3H, m), 3.07(2H, t), 2.68-2.64(2H, m), 1.90(2H, d),1.66-1.54(3H, m), 0.92-0.86(6H, m)

MP: 139-142° C.

EXAMPLE 1555-Chloro-N-(1-methylethyl)-6-[4-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one hydrochloride (WO 9502405)(0.13 g) and the product from example 117 step (i) (0.13 g) according tothe method of example 115 step (ii). Yield 0.04 g as a solid.

MS: APCI(+ve) 429 (M+1)

1H NMR: δ (DMSO-d6) 8.64(1H, d), 8.25(1H, d), 8.18(1H, d), 7.40(1H, d),7.12-7.03(3H, m), 4.52(2H, s), 4.37-4.32(1H, m), 4.11-4.04(3H, m),3.03(2H, t), 2.77-2.6(2H, m), 1.82(2H, d), 1.16(6H, d)

MP: 85-88° C.

EXAMPLE 156N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The product from example 8 step (i) (0.05 g) was reacted withisopropylamine (0.02 ml) using the method of example 115 step (i) inN,N-dimethylformamide (2 ml). Purification was by chromatography elutingwith (2:1) ethyl acetate/isohexane. Yield 0.035 g as a solid.

MS: APCI(+ve) 439(M+1)

1H NMR: δ (CDCl₃) 8.17(1H, m), 7.93-7.90(1H, m), 7.38-7.09(5H, m),5.92-5.90(1H, d), 5.10(2H, s), 4.32-4.16(2H, m), 3.53-3.49(2H, m),3.17-3.10(2H, m), 2.90-2.80(2H, m), 1.96-1.93(2H, m), 1.28-1.26(6H, d)

MP: 193-195° C.

EXAMPLE 157N-[(1S)-1-(Aminocarbonyl)-2-methylbutyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The product from example 8 step (i) (0.05 g) was reacted with(S)-leucinamide hydrochloride (0.025 g) using the method of example 115step (i) in N,N-dimethylformamide (2 ml). Purification was bychromatography eluting with ethyl acetate. Yield 0.025 g as a solid.

MS: APCI(+ve) 510(M+1)

1H NMR: δ (CDCl₃) 8.29-7.09(6H, m), 6.90(1H, d), 6.22(1H, br s),5.56(1H, br s), 5.10(2H, s), 4.73-4.11(2H, m), 3.50-2.80(6H, m),1.97-1.70(5H, m), 1.27-1.22(1H, m), 0.99(6H, d)

MP: 146-149° C.

EXAMPLE 158N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)-5-pyrimidine-5-carboxamide.

(i)N-(1-Methylethyl)-2-chloro-4-(trifluoromethyl)pyriniidine-5-carboxamide.

2-Chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (1.0 g) indry N,N-dimethylformamide (5 ml) was treated with isopropylamine (0.4ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 min,diluted with water, extracted with ethyl acetate, dried, and evaporatedunder reduced pressure. Purification was by chromatography eluting with50% ethyl acetate/dichloromethane. Yield 0.74 g as a solid.

MS: APCI(+ve) 268(M+1)

(ii)N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl]piperidin-1-yl]-4-(trifluoromethyl)-5-pyrimidine-5-carboxamide.

The title compound was prepared from the product from step (i) (0.092 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(0.1 g) using the method of example 115 step(ii). Purification was bychromatography eluting with (1:3) ethyl acetate/dichloromethane. Yield0.110 g as a solid.

MS: APCI(+ve) 464(M+1)

1H NMR: δ (CDCl₃) 8.58(1H, s), 7.38-7.08(4H, m), 5.62-5.60(1H, d),5.10-5.05(4H, m), 4.29-4.15(2H, m), 3.06-2.62(4H, m), 1.99-1.95(2H, d),1.25-1.24(6H, d)

MP: 217-219° C.

EXAMPLE 1593-Chloro-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

(i) 1,1-Dimethylethyl3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzoate

The product was prepared from 3-nitro-4-chloro-t-butylbenzoate (0.96 g)and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride(1.0 g) using the method of example 115 step (ii). Purification was bychromatography eluting with 50% ethyl acetate/isohexane. Yield 2.1 g asan oil.

MS: APCI(+ve) 454(M+1)

(ii)3-Amino-1,1-dimethylethyl-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzoate

The product from step (i) (1.9 g) was dissolved in glacial acetic acid(20 ml) and treated with reduced iron powder (1.9 g). The mixture wasstirred vigorously for 2 h at room temperature. The mixture was filteredthrough a pad of celite and the filtrate evaporated under reducedpressure. Purification was by chromatography eluting with (1:5) ethylacetate/dichloromethane. Yield 0.975 g as a solid.

MS: APCI(+ve) 424(M+1)

(iii) 3-Chloro-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

Product from step (ii) (0.39 g) was treated with copper(II) chloride(0.148 g), isoamylnitrite (0.25 ml) in acetonitrile (10 ml) and heatedto 65° C. for 4 h. The reaction mixture was evaporated under reducedpressure to an oil. The oil was treated with trifluoroaceticacid/dichloromethane (1:1) and stirred at room temperature for 2 h thenevaporated under reduced pressure. The residue was dissolved inN,N-dimethylformnamide (5 ml), bromo-tris-pyyrolidino-phosphoniumhexafluorophosphate (0.116 g), isopropylamine (0.054 ml) andN,N-diisopropylethylamine (0.06 ml) were added and stirred at roomtemperature for 16 h. The mixture was evaporated under reduced pressure.Purification was by chromatography eluting with (1:3) ethylacetate/dichloromethane. Yield 0.017 g as a solid.

MS: APCI(+ve) 428(M+1)

1H NMR: δ (CDCl₃) 7.76-7.06(7H, m), 5.82-5.80(1H, d), 5.10(2H, s),4.31-4.15(2H, m), 3.65-3.62(2H, m), 2.95-2.82(4H, m), 1.98-1.95(2H, d),1.27-1.25(6H, d).

EXAMPLE 1603-Amino-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was prepared from the product of example 156 usingthe method described in example 159 step (ii). Yield 0.6 g as a solid.

MS: APCI(+ve) 409(M+1)

1H NMR: δ (DMSO-d6) 7.89-7.86(1H, d), 7.39-6.91(7H, m), 5.15(2H, s),4.84-4.82(2H, s), 4.08-3.99(2H, m), 3.23-3.21(2H, m), 2.77-2.67(4H, m),1.88-1.85(2H, m), 1.19-1.12(6H, d)

EXAMPLE 161N-(1-Methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

(i) 1,1-Dimethylethyl4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzoate

A solution of sodium nitrite (0.11 g) in water (1 ml) was added to astirred solution of the product from example 159 step (ii) (0.456 g) inacetonitrile (10 ml) at room temperature. After 1 h a solution of ironsulphate (0.3 g) in N,N-dimethylformamide (20 ml) was added and themixture stirred for a further 30 min. The mixture was partitionedbetween ethyl acetate and water, the organics dried and evaporated underreduced pressure. Purification was by chromatography eluting with 20%ethyl acetate/isohexane. Yield 0.29 g as an oil.

MS: APCI(+ve) 409(M+1)

(ii)N-(1-Methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

A solution of the product from step (i) (0.29 g) in a mixture oftrifluoroacetic acid (10 ml) and dichloromethane (10 ml) was stirred atroom temperature for 1 h. The solution was evaporated under reducedpressure, the residue dissolved in N,N-dimethylformamide thenbromo-tris-pyyrolidino-phosphonium hexafluorophosphate (0.16 g),isopropylamine (0.06 ml) and N,N-diisopropylethylamine (0.06 ml) added.The solution was stirred at room temperature for 16 h then evaporatedunder reduced pressure. Purification was by chromatography eluting with(1:5) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.

MS: APCI(+ve) 394(M+1)

1H NMR: δ (DMSO-d6) 7.89-6.95(9H, m), 5.13(2H, s), 4.15-3.97(4H, m),3.01-2.95(2H, m), 2.59-2.49(2H, m), 1.85-1.82(2H, d), 1.13(6H, d)

EXAMPLE 162N-[(1S)-1-(Aminocarbonyl)-3-methylbutyl]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was prepared from the product of example 161 step (i)(0.06 g) and (S)-leucinamide hydrochloride (0.056 g) using the method ofexample 161 step (ii). Purification was by chromatography eluting with(5:1) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.

MS: APCI(+ve) 465(M+1)

1H NMR: δ (DMSO-d6) 8.04-6.92(11H, m), 5.13(2H, s), 4.44-3.99(4H, m),3.03-2.93(2H, m), 2.60-2.49(2H, m), 1.85-1.50(5H, m), 0.88(6H, d)

EXAMPLE 1633-(Ethylamino)-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

Sodium triacetoxyborohydride (0.1 g) was added to a solution of theproduct from example 160 (0.1 g), acetaldehyde (0.015 ml), acetic acid(1 drop) in N,N-dimethylformamide (10 ml). The reaction mixture wasstirred at room temperature for 16 h. The mixture was diluted withwater, extracted with ethyl acetate, dried, and evaporated under reducedpressure. Yield 0.035 g.

MS: APCI(+ve) 437(M+1)

1H NMR: δ (DMSO-d6) 7.96-6.98(8H, m), 5.15(2H, s), 4.73-4.70(1H, t),4.13-3.99(2H, m), 3.25-3.14(4H, m), 2.81-2.64(4H, m), 1.90-1.88(2H, m),1.26-1.14(9H, m)

EXAMPLE 1643-(Diethylamino)-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was obtained from the reaction mixture in example163. Yield 0.052 g.

MS: APCI(+ve) 465(M+1)

1H NMR: δ (DMSO-d6) 7.97-6.90(8H, m), 5.15(2H, s), 4.11-3.99(2H, m),3.86-3.83(2H, m), 3.31-3.18(4H, m), 2.72-2.63(4H, m), 1.86(2H, m),1.19-1.14(6H, d), 1.03-0.95(6H, m)

EXAMPLE 165N-(1-Methylethyl)-3-[(methylsulfonyl)amino]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide

The title compound was prepared from the product of example 160 (0.1 g)and methanesulphonylchloride (0.02 ml) in dichloromethane (10 ml) at 0°C. in the presence of 2,6-lutidine (0.085 ml). The reaction mixture wasstirred at room temperature for 16 h. The mixture was evaporated,dissolved in ethyl acetate, washed with water, dried, and evaporatedunder reduced pressure. Purification was by chromatography eluting with(3:1) ethyl acetate/isohexane. Yield 0.066 g as a solid.

MS: APCI(+ve) 487(M+1)

1H NMR: δ (DMSO-d6) 8.63(1H,s), 8.16-8.13(1H, d), 7.76-7.10(7H, m),5.16(2H, s), 4.14-3.99(2H, m), 3.27-3.23(2H, m), 3.19(3H, s),2.93-2.70(4H, m), 1.89-1.86(2H, m), 1.17-1.14(6H, d)

EXAMPLE 1665-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-1,3-benzoxazol-3(2H)-yl)piperidin-1-yl]pyridine-3-carboxantide

(i) 1,1-Dimethylethyl4-(2-oxo-1,3-benzoxazol-3(2H)-yl)piperidine-1-carboxylate

2-Benzoxazolinone (1 g) was added to a cooled solution oftriphenylphoshine (2.13 g) and diethylazodicarboxylate (1.28 ml) in drytetrahydrofuran (20 ml). After 10 min at 0° C.,N-(t-butoxy)-4-hydroxypiperidine (1.63 g) (Tetrahedron Letters, 1996,6439-6442) was added portionwise. The reaction mixture was stirred atroom temperature for 16 h. The solution was diluted with water,extracted with ethyl acetate, dried and evaporated under reducedpressure. Purification was by chromatography eluting with (1:2)diethylether/isohexane. Yield 0.5 g as an oil.

MS: APCI(+ve) 219(M+1)-BOC

(ii) 3-Piperidin-4-yl-1,3-benzoxazol-2(3H)-one, trifluoroacetic acidsalt

The product from step (i) (0.5 g) was stirred at room temperature in(1:1) trifluoroacetic acid/dichloromethane (10 ml) for 30 min. Thereaction mixture was evaporated under reduced pressure to give an oil.Used crude.

MS: APCI(+ve) 219(M+1)

(iii)5-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-1,3-benzoxazol-3(2H)-yl)piperidin-1-yl]pyridine-3-carboxamide

The title compound was prepared from the product of example 117 step(i)(0.53 g) and the product from step (ii) by the method described inexample 115 step (ii). Purification was by chromatography eluting with50% ethyl acetate/isohexane. Yield 0.28 g as a solid.

MS: APCI(+ve) 415(M+1)

1H NMR: δ (DMSO-d6) 8.66-7.12(7H, m), 4.44-4.38(1H, m), 4.10-4.05(3H,m), 3.09-3.03(2H, t), 2.45-2.35(2H, m), 1.95-1.92(2H, m), 1.17-1.15(6H,d)

MP: 162-168° C.

EXAMPLES 167-169

(i) 4-Chloro-N-(1-methylethyl)-3-nitrobenzamide

Isopropylamine (1.28 ml) was added dropwise to a stirred solution of4-chloro-3-nitrobenzoylchloride (3.0 g) and triethylamine (2.8 ml) indichloromethane (30 ml) at room temperature. After 2 h the mixture waspartitioned between ethyl acetate and water, the organics dried andevaporated under reduced pressure. Yield 2.87 g.

1H NMR: δ (DMSO-d6) 8.58(1H, d), 8.51(1H, d), 8.15(1H, dd), 7.89(1H, d),4.14-4.06(1H, m), 1.18(6H, d)

(ii) Examples 167-169

A solution of the product from step (i) (1 mg),N,N-diisopropylethylamine (3 equiv.), the appropriate amine (1.5 equiv.)in 1-methyl-2-pyrrolidinone (0.16 ml) were heated at 65° C. for 30 h.The reaction mixture was evaporated to dryness and the residue dissolvedin dimethylsulphoxide (0.4 ml).

EXAMPLE 167N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]benzamide

MS: APCI(+ve) 436(M+1)

EXAMPLE 1684-[4-(7-Chloro-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1-methylethyl-3-nitrobenzamide

MS: APCI(+ve) 472(M+1)

EXAMPLE 1695-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)piperidin-1-yl]pyridine-3-arboxamide

The title compound was prepared from1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one (0.03 g) and the productfrom example 117 step (i) (0.03 g) by the method of example 115 step(ii). Purification was by chromatography eluting with 50% ethylacetate/I-hexane. Yield 0.017 g as a white solid.

MS: APCI(+ve) 427 (M+1)

1H NMR: δ (DMSO-d6) 8.49(1H, d), 7.98(1H, d), 7.20(3H, m), 7.02(1H, t),5.83(1H, d), 4.50(1H, m), 4.20(3H, m), 2.98(2H, t), 2.80(4H, m),2.60(2H, t) 1.83(2H, m), 1.25(6H, d)

EXAMPLE 1704-[4-(2,2-Dioxido-3,4-dihydro-1H-2,1,3-benzothiadiazin-1-yl)piperidin-1-yl]-N-(1-methylethyl)-3-nitrobenzamide

The title compound was prepared from1-Piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine 2,2-dioxide(Chem. Pharm. Bull. (1985), 33(3), 1104-15) (0.05 g) and the productfrom example 167 step (i) (0.05 g) by the method of example 115 step(ii). Purification was by chromatography eluting with ethyl acetate.Yield 0.03 g as a white solid.

MS: APCI(+ve) 474 (M+1)

1H NMR: δ (DMSO-d6) 8.32 (2H, m), 8.00 (1H, d), 7.72 (1H, t), 7.30 (2H,m), 7.20 (2H, d), 7.10 (1H, t), 4.41(2H, d), 4.10 (3H, m), 3.40 (1H, m),3.04 (2H, t), 2.00 (4H, m), 1.15 (6H,d).

EXAMPLE 1711-(1-{2-Chloro-4-[(1H-imidazol-2-ylmethyl)amino]phenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

The product of example 120 step (ii) (0.25 g) was dissolved in1-methyl-2-pyrrolidinone (6 ml) and this solution was treated with2-imidazolecarboxaldehyde (0.1 g) followed by acetic acid (0.13 g) andthen sodium triacetoxyborohydride (0.37 g). the reaction mixture wasstirred at room temperature for three days. At the end of this time themixture was poured in to excess aqueous dilute hydrochloric acid, thissolution was allowed to stand for 10 minutes before being basified byaddition of excess aqueous sodium bicarbonate. The mixture was extractedwith ethyl acetate, the organic layer was washed with water, dried andevaporated under reduced pressure. Purification was by chromatographyeluting with methanol/chloroform (7/93). Yield 0.05 g as a solid.

MS: APCl (=ve) 438 (M+1)

1H NMR: δ (DMSO-d6) 11.84 (1H, s), 7.41 (1H, t), 7.31-7.27(2H, m),7.11(1H, t), 6.97(1H, d), 6.92(2H, s), 6.73(1H, d), 6.57(1H, q),6.06(1H, t), 5.14(2H, s), 4.19(2H, d), 3.98-3.93(1H, m), 3.15(2H, d),2.78-2.63(4H, m) 1.83(2H, d)

MP: 222-224° C.

Pharmacological Analysis

Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP)are known to be agonists of the P2X₇ receptor, effecting the formationof pores in the plasma membrane (Drug Development Research (1996),37(3), p.126). Consequently, when the receptor is activated using bbATPin the presence of ethidium bromide (a fluorescent DNA probe), anincrease in the fluorescence of intracellular DNA-bound ethidium bromideis observed. The increase in fluorescence can be used as a measure ofP2X₇ receptor activation and therefore to quantify the effect of acompound on the P2X₇ receptor.

In this manner, each of the title compounds was tested for antagonistactivity at the P2X₇ receptor. Thus, the test was performed in 96-wellflat bottomed microtitre plates, the wells being filled with 100 μl oftest solution comprising 80 μl of a suspension of THP-1 cells (2.5×10⁶cells/ml) containing 10⁻⁴M ethidium bromide, 10 μl of a high potassiumbuffer solution containing 10⁻⁵M bbATP, and 10 μl of the high potassiumbuffer solution containing 1×10⁻⁴M test compound (in 10% v/v DMSO). Theplate was covered with a plastic lid and incubated at 37° C. for onehour. The plate was then read in a Spectromax Gemini Fluorescent platereader excitation 525 nm, emission 610 nm, slit widths: Ex 15 nm, Em 20nm. For the purposes of comparison, bbATP (a P2X₇ receptor agonist) andN-(5-methoxy-2-methylphenyl)-tricyclo[3.3.1.1^(3,7)]decane-1-acetamide(WO99/29660, a P2X₇ receptor antagonist) were used separately in thetest as controls. From the readings obtained, a pIC₅₀ figure wascalculated for each test compound, this figure being the negativelogarithm of the concentration of test compound necessary to reduce thebbATP agonist activity by 50%. The pIC₅₀ was then corrected using amodified Cheng Prusoff calculation based on agonist A₅₀ (Trends inPharmacological Sciences (1993), 14(4), 110-2). Each of the compounds ofthe Examples demonstrated antagonist activity, having a pIC₅₀figure>5.00.

What is claimed is:
 1. A compound of formula (I):

where A is phenyl or a 5- or 6-membered heterocyclic ring having one ortwo heteroatoms selected from O, N or S; and optionally substituted byC₁₋₆alkyl, halogen, nitro, amino, alkylamino, CF₃, SO₂Me, NHSO₂Me orcyano; B is C═O, NH or SO₂; X is O, (CH₂)p where p is 1; Y is O, or CH₂,provided that X and Y connot both be O or CH₂; Z is C═O; R is hydrogenor C₁₋₆alkyl; R¹ is hydrogen, halogen; R² is phenyl optionallysubstituted by CO₂H, CO₂alkyl, CONH₂ or R² is OH, NHR³,NHCH(R⁴)(CHR⁵)_(n)R⁶, NH—R⁷—R⁸, SO₂NHalkyl, NHCOalkyl, NHSO₂alkyl,morpholine, NR⁹R¹⁰, piperazine substituted by phenyl, alkoxyphenyl,pyridyl or fluorophenyl; n is 0, 1 or 2; R³ is hydrogen, a bi- ortricyclic saturated ring system optionally having a nitrogen atom,piperidinyl, alkylpyrollidine, ethynylcyclohexyl, a 5-membered aromaticring having 2 or 3 heteroatoms selected from N or S, C₄₋₆ cycloalkyloptionally substituted by alkyl, cyano or hydroxy, or C₁₋₈ alkyloptionally having an oxygen atom in the alkyl chain and being optionallysubstituted by one or more substituents selected from ethynyl, cyano,fluoro, di-alkylamino, hydroxy, thioalkyl, CO₂R¹¹ or CONH₂; R⁴ ishydrogen or alkyl optionally substituted by hydroxy or alkoxy; R⁵ ishydrogen or hydroxy; R⁶ is alkyl, CO₂R¹¹, NHCO₂R¹², CONH₂ or a 5 or6-membered saturated ring having an oxygen atom, a 5-memberedheterocyclic ring having one or two heteroatoms selected from O, N or S,or phenyl optionally substituted by one or more groups selected fromalkyl, hydroxy, amino, alkoxy, or nitro; R⁷ is a cyclopentane ring; R⁸is phenyl; R⁹ and R¹⁰ are independently hydrogen, benzyl, alkenyl,cycloalkyl, alkyl optionally substituted by hydroxy, alkoxy, cyano,dialkylamino, phenyl, pyridyl or CO₂R¹¹ or R⁹ and R¹⁰ together form a 5-to 7-membered saturated or partially saturated ring optionally having afurther heteroaton selected from O, N or S and optionally substituted byone or more groups selected from alkyl (optionally having an oxygen atomin the chain and optionally substituted by hydroxy), COalkyl, CO₂R¹¹,COR¹³R¹⁴, CHO or piperidine, R¹¹ is hydrogen or alkyl; R¹² is alkyl; andR¹³ and R¹⁴ are independently hydrogen or alkyl, or a pharmaceuticallyacceptable salt or solvate thereof.
 2. A compound according to claim 1in which A is phenyl optionally substituted by C₁₋₆alkyl, halogen,nitro, amino, alkylamino, CF₃, SO₂Me, NHSO₂Me or cyano.
 3. A compoundaccording to claim 1 in which B is C═O.
 4. A compound according to claim1 in which X is CH₂, Y is O and Z is C═O.
 5. A compound according toclaim 1 in which R is hydrogen.
 6. A compound according to claim 1 inwhich R¹ is hydrogen.
 7. A compound according to claim 1 in which R² isNR⁹R¹⁰ where one of R⁹ or R¹⁰ is hydrogen and the other is alkyl.
 8. Acompound according to claim 1 which is:2-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoicacid,1-{1-[2-Nitro-4-(phenylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,Methyl2-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzoate,2-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)benzamide,Methyl2-({4-[4-(7-chloro-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-3-nitrophenyl}carbonyl)benzoate,N-(1,1-Dimethylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1R)-2-Hydroxy-1-(phenylmethyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,Methyl2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide,N-[2-(4-Aminophenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,Ethyl(2S)-3-methyl-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]butanoate,Methyl3-hydroxy-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate,N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-phenylethyl)benzamide,N-[(4-Aminophenyl)methyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-thien-2-ylethyl)benzamide,N-[3-(Dimethylamino)-2,2-dimethylpropyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-{[2,4-Bis(methyloxy)phenyl]methyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Bicyclo[2.2.1]hept-2-yl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(2-Fluoroethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-N-[(3-nitrophenyl)methyl]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-{[3,4,5-tris(methyloxy)phenyl]methyl}benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-phenylcyclopropyl)benzamide,N-[2-Hydroxy-1-(hydroxymethyl)-1-methylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(2-piperidin-1-ylethyl)benzamide,N-(1,3-Dimethylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Methylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Methylhexyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(3-Methylbutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(2-Aminophenyl)methyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[2-(Ethylthio)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(4-Methylcyclohexyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-{2-Hydroxy-1-[(methyloxy)methyl]-2-phenylethyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Cyclopropyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,N-(1-Methylpropyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,1,1-Dimethylethyl2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]ethylcarbamate,N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-{[4-(Methyloxy)phenyl]methyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[2-(1H-Imidazol-4-yl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1S)-1-(Hydroxymethyl)propyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-[1-(phenylmethyl)piperidin-4-yl]benzamide,N-[(1R)-1-(Hydroxymethyl)propyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(4-Hydroxybutyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-tricyclo[3.3.1.1˜3,7˜]dec-1-ylbenzamide,N-[(1S,2S)-2-Hydroxycyclohexyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(2-Hydroxy-1-methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-{2-[(2-Hydroxyethyl)oxy]ethyl}-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[1-(Hydroxymethyl)butyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(2-Amino-2-oxoethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[1-(4-Fluorophenyl)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(3-phenylpropyl)benzamide,N-[(1S,2R)-2-Hydroxycyclohexyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,Ethyl3-hydroxy-2-[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)amino]propanoate,N-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,1-{1-[4-(Morpholin-4-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,N,N-Dimethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N,N-Bis(2-hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(2-Hydroxyethyl)-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(2-Hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,1-(1-{2-Nitro-4-[(4-phenylpiperazin-1-yl)carbonyl]phenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Ethyl-N-(2-hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,1-[1-(4-{[4-(4-Fluorophenyl)piperazin-1-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-{1-[4-(Azepan-1-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,N,N-Diethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[2-(Dimethylamino)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,N-Butyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylnethyl)benzamide,1-{1-[2-Nitro-4-(piperidin-1-ylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,Ethyl[({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)(phenylmethyl)amino]acetate,N-(2-Hydroxyethyl)-N-(1-methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,1-(1-{2-Nitro-4-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-{1-[2-Nitro-4-(pyrrolidin-1-ylcarbonyl)phenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,N-(2-Hydroxyethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-pentylbenzamide,N-[2-(Diethylamino)ethyl]-N-ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Ethyl-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,(2S)-1-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)pyrrolidine-2-carboxamide,N-(2-Cyanoethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,1-(1-{4-[(3,5-Dimethylpiperidin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-[1-(4-{[(2R,6S)-2,6-Dimethylmorpholin-4-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-{1-[4-({4-[2-(Methyloxy)phenyl]piperazin-1-yl}carbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-{1-[2-Nitro-4-(thiomorpholin-4-ylcarbonyl)phenyl]piperidin-4yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-(1-{4-[(4-{2-[(2-Hydroxyethyl)oxy]ethyl}piperazin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,N-Ethyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(pyridin-4-ylmethyl)benzamide,N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-prop-2-ynylbenzamide,1-(1-{4-[(4-Acetylpiperazin-1-yl)carbonyl]-2-nitropheny}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-[1-(4-{[2-(Hydroxymethyl)piperidin-1-yl]carbonyl}-2-nitrophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one,4-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperazine-1-carbaldehyde,N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(phenylmethyl)benzamide,Ethyl4-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperazine-1-carboxylate,Ethyl1-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-4-carboxylate,1-({3-Nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-3-carboxamide,1-(1-{4-[(4-Methylpiperazin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-{1-[4-(2,5-Dihydro-1H-pyrrol-1-ylcarbonyl)-2-nitrophenyl]piperidin-4-yl}-1,4-dihydro-2H-3,1-benzoxazin-2-one,N-Ethyl-N-(2-methylprop-2-enyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N,N-Bis(cyanomethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-Butyl-N-(cyanomethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N,N-Bis(2-hydroxypropyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,1-(1-{4-[(4-Hydroxypiperidin-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,1-(1-{4-[(2,5-Dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-2-nitrophenyl}piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one,N-Methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-propylbenzamide,N-(2-Amino-2-oxoethyl)-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N,N-Diethyl-1-({3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}carbonyl)piperidine-3-carboxamide,N-Cyclohexyl-N-methyl-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[2-(Methyloxy)ethyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,5-Chloro-N-(1-methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzenesulfonamide,1-[1-(4-Amino-2-chlorophenyl)piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one,3-Cyano-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-2-methylpropanamide,N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}propane-2-sulfonamide,N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-cyanocyclopropanecarboxamide,(2S)-N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-methylpyrrolidine-2-carboxamide,5-Chloro-N-(1-methylethyl)-6-[4-(4-methyl-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,±-5-Chloro-N-(1-methylethyl)-6-[(cis)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,±-5-Chloro-N-(1-methylethyl)-6-[(trans)-3-methyl-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,2-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide,2-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide,2-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1H-pyrazol-3-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(4-Hydroxycyclohexyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-[1-(Hydroxymethyl)propyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(3-Hydroxy-2,2-dimethylpropyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,2-[4-(2-Oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(tetrahydrofuran-2-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-Cyclobutyl-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-Cyclopentyl-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-[2-(1H-Imidazol-4-yl)ethyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(1-Ethynylcyclohexyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-[(1R)-1-(Hydroxymethyl)-2-methylpropyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(2-Hydroxy-1,1-dimethylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamnide,N-(1,1-Diethylprop-2-ynyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(2-Hydroxy-1-methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-[1-Methyl-2-(methyloxy)ethyl]-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxamide,N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyrimidine-5-carboxamide,N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-1,3-thiazole-4-carboxamide,N-(1-Methylethyl)-3-(methylsulfonyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1R)-1-(Aminocarbonyl)-2-methylpropyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxzin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,5-Chloro-N-(2-hydroxy-1-methylethyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,5-Chloro-N-(1,1-dimethylprop-2-ynyl)-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,N-(2-Amino-1-cyano-2-oxoethyl)-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,N-[(1R)-1-(Aminocarbonyl)-3-methylbutyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,N-[(1S)-1-(Aminocarbonyl)-2-methylpropyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,N-[(1S)-1-(Aminocarbonyl)-3-methylbutyl]-5-chloro-6-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]pyridine-3-carboxamide,5-Chloro-N-(1-methylethyl)-6-[4-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)piperidin-1-yl]pyridine-3-carboxamide,N-(1-Methylethyl)-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1S)-1-(Aminocarbonyl)-2-methylbutyl]-3-nitro-4-[4-(2-oxo-2H-3,1-benzoxazin-1-yl)piperidin-1-yl]benzamide,N-(1-Methylethyl)-2-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-4-(trifluoromethyl)-5-pyrimidine-5-carboxamide,3-Chloro-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-Amino-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-[(1S)-1-(Aminocarbonyl)-3-methylbutyl]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-(Ethylamino)-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,3-(Diethylamino)-N-(1-methylethyl)-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,N-(1-Methylethyl)-3-[(methylsulfonyl)amino]-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]benzamide,4-[4-(7-Chloro-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]-N-(1-methylethyl)-3-nitrobenzamide,or a pharmaceutically acceptable salt or solvate thereof.
 9. Apharmaceutical composition comprising a compound according to claim 1 incombination with a pharmaceutically acceptable diluent, adjuvent orcarrier.
 10. A process for the preparation of a compound of formula (I)which comprises reaction of a compound of formula (II):

where R, R¹, X, Y and Z are as defined in claim 1 or a protectedderivative thereof, with a compound of formula (III):

where B and R² are as defined in claim 1 or a protected derivativethereof, and L is a leaving group, and optionally thereafter in anyorder: converting one or more functional groups into further functionalgroups removing any protecting groups forming a pharmaceuticallyacceptable salt or solvate.
 11. A method of treating rheumatoidarthritis in a warm blooded animal in need thereof which comprisesadministering to said animal a therapeutically effective amount of acompound according to any one of claims 1 to
 8. 12. A method of treatingchronic obstructive pulmonary disease in a warm blooded animal in needthereof which comprises administering to said animal a therapeuticallyeffective amount of a compound according to any one of claims 1 to 8.13. A method of treating osteoarthritis in a warm blooded animal in needthereof which comprises administering to said animal a therapeuticallyeffective amount of a compound according to any one of claims 1 to 8.14. A method of treating asthma in a warm blooded animal in need thereofwhich comprises administering to said animal a therapeutically effectiveamount of a compound according to any one of claims 1 to 8.